Amino acids are necessary building blocks in the synthesis of proteins by the human body, derived principally from dietary sources of proteins. The human body uses nineteen separate L-configuration amino acids to synthesize proteins. Some of these amino acids are referred to as “essential amino acids” because the body cannot independently synthesize them. Other amino acids are not “essential” because the body can synthesize them.
The digestion of dietary proteins to amino acids starts in the stomach, thanks to the combined activity of pepsinogen, pepsine and hydrochloric acid leading to oligopeptides. The digestion continues in the duodenum after transit from the stomach through the pylorus, where the combined activity of biliary secretion, bicarbonates and pancreatic enzymes is able to produce individual amino acids. Montgomery R. et al., 1988; Baracos, 2004. The liberated amino acids are then absorbed from the small intestine into the portal vein according to active stereospecific transport processes specific for amino acids. The secretion into the intestine of amino acids is a concomitant mechanism. Dipeptides and tripeptides can also be absorbed from the small intestine, but they too are eventually hydrolyzed into amino acids in the enterocyte. These processes are largely pH dependent. When food is ingested, the stomach secretes hydrochloric acid and the pH decreases to around 2. After the pyloric valve, the pH progressively increases from 4 to approximately 7 as a consequence of alkaline biliary secretion. A buffer system operates to prevent pH values larger than approximately 7.5-7.8.
The time required to digest dietary proteins is the sum of the time spent in the gastric emptying phase and the time required for hydrolysis in the small intestine. The time needed for both of these processes can vary depending on food intake, protein intake, illness, and concomitant drug treatments, with food intake being the most common determining factor. Amidon et al., 1995 reports a gastric emptying time of approximately 3.5 hours after a high fat meal, approximately 1.5 hours after an average meal, and approximately 10 to 20 minutes after 250 ml of water. Keohane et al., 1985 reports the time required to hydrolyze amino acids in the small intestine, on average, is approximately three hours, and that this time varies for individual proteins and amino acids. This hydrolysis starts to occur immediately after gastric emptying, after transit through the pyloric valve, and lasts for several hours in the first tract of the small intestine, namely the jejunum.
Amino acids are commonly administered as supplements to the diet to facilitate protein synthesis, particularly where increases in muscle mass are intended. Specially formulated combinations of amino acids are also administered to support the nutritional health of individuals with special dietary intake limitations and requirements. In phenylketonuria, for example, the body is unable to metabolize phenylalanine to tyrosine due to the lack of necessary enzymes. The phenylalanine instead decomposes to several toxic by-products. Montgomery et al., 1988; Waisbren et al., 2007.
Phenylalanine is an essential amino acid that is normally metabolized to tyrosine by the enzyme phenylalanine hydroxylase. In phenylketonuria this enzyme is absent or not functioning properly, and the phenylalanine is decarboxylated to various compounds, three of them being toxic: phenylpyruvate, phenyl lactate and phenyl acetate. Because of this metabolic inhibition, the dietary intake of phenylalanine must be reduced while providing the amino acid tyrosine with the diet as it is indispensable. Ney D. M. et al., 2014; Dioguardi, 2011; Waisbren et al., 2007.
An effective management strategy for phenylketonuria consists of specially formulated amino acid formulations that omit phenylalanine while supplementing tyrosine. Because phenylalanine cannot be removed from most dietary sources of protein, these amino acid supplements will usually take the place of dietary proteins, which are eliminated from the diet entirely. Vliet Van D. et al., 2014. These patients can, however, also be treated with a carefully controlled diet of proteins that have very little phenylalanine. Gropper S. S. et al., 1991.
Examples of amino acid formulations sold for the management of phenylketonuria include formulations sold as Antifen™, Nutricia XP2™ (Maxamaid) and Milupa PKU2™ (Secunda). Nutricia XP2™ and Milupa PKU2™ also contain vitamins and minerals. The following Table A gives the formulations of these products, based on about 100 g of amino acids in each formulation, omitting the vitamin and mineral content.
TABLE AAntifen ™ 1Nutricia XP2 ™ 2Milupa PKU2 ™ 3ComponentgggAlanine7.604.054.03Arginine7.837.203.32Aspartic Acid11.306.709.48Cystine1.172.662.25Glutamic Acid——19.92Glutamine12.504.94—Glycine4.806.352.25Histidine2.734.112.25Isoleucine3.236.355.69Leucine7.2010.869.37Lysine8.197.376.64Methionine2.141.732.25Proline4.897.709.01Serine8.104.664.98Taurine0.251.17—Threonine3.805.334.51Tryptophan1.252.141.66Tyrosine7.509.645.57Valine5.406.976.64Carnitine0.110.060.181 http://www.dmfmetabolic.it/wp-content/uploads/2013/10/AntifenIntegrale.pdf2 http://www.nutricia.it/prodotti/xp2-maxamaid/3 http://www.nutricia.it/prodotti/pku-2-secunda/
Other conditions for which specially formulated amino acid preparations are manufactured and administered, using the same strategy to provide all essential and non-essential amino acids but omitting amino acids that the body is unable to metabolize, include tyrosinemia, leucinosis, methylmalonic acidemia, homocistinuria, hyperglycinemia, isovaleric acidemia, propionic acidemia, and glutaric acidemia (types II, IIA or IIB).
Free amino acids potentially present numerous disadvantages over naturally occurring proteins, due to the rapid absorption of the amino acids, imposing a higher dietary acid load, particularly when higher doses are administered.
In addition the taste and the odor and taste of some commercial amino acid formulations is not good, which makes them extremely difficult for many people to ingest on a regular basis, particularly infants and children. In addition, these formulations are released immediately when ingested, leading to a very different absorption pattern than when proteins are ingested.
One object of the present invention is to limit the amino acid catabolism caused when free amino acids are ingested and overwhelm the body's metabolic capacity.
Another object of the present invention is to improve the taste of amino acid formulations when orally ingested.
Still another object of the present invention is to provide unique dosage forms of amino acids that can be eaten directly without the need for reconstitution.
Yet another object of the present invention is to provide formulations of amino acids with modified release properties, that more closely mimic the absorption pattern of proteins when orally ingested.